How VE-PTP and Tie-2 regulate endothelial cell junctions in VE-cadherin dependent and independent ways

血管内皮细胞特异性蛋白酪氨酸磷酸酶(VE-PTP)是一种受体型酪氨酸磷酸酶(R-PTP)，是内皮细胞连接、血管通透性和白细胞外渗的主要调节因子。我们已经证明，这种磷酸酶与黏附分子VE-钙粘附素结合并调节其功能，VE-钙粘附素对内皮连接的完整性至关重要。此外，我们发现VE-PTP调节酪氨酸激酶受体Tie-2的活性，从而稳定连接。因此，VE-PTP在稳定内皮细胞连接和抑制炎症诱导的血管漏形成方面是一个有价值的药理靶点。事实上，VE-PTP的高度特异性抑制剂AKB9778能够防止小鼠炎症模型中渗漏的形成，目前已在糖尿病患者视网膜病变的II期试验中成功测试。这项建议的目的是阐明VE-PTP抑制支持血管完整性的详细机制。我们将分析VE-PTP对Tie-2和VE-cadherin的影响是如何相互联系的，以及VE-PTP还有哪些底物和信号靶点参与内皮连接的调节。

The endothelial specific Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) is a receptor type tyrosine phosphatase (R-PTP) which is a major regulator of endothelial junctions, vascular permeability and leukocyte extravasation. We have shown that this phosphatase associates with and regulates the function of VE-cadherin, an adhesion molecule, which is of central importance for the integrity of endothelial junctions. In addition, we found that VE-PTP regulates the activity of the tyrosine kinase receptor Tie-2, which stabilizes junctions. Consequently, VE-PTP is a valuable pharmacological target for the stabilization of endothelial junctions and for the inhibition of inflammation induced vascular leak formation. Indeed, the highly specific inhibitor of VE-PTP, AKB9778, is able to protect from leak formation in inflammation models in the mouse and is presently tested successfully in phase II trials on diabetic retinopathy in patients. The purpose of this proposal is to elucidate the detailed mechanisms by which the inhibition of VE-PTP supports vascular integrity. We will analyze how the effects of VE-PTP on Tie-2 and VE-cadherin relate to each other and which other substrates and signaling targets of VE-PTP are involved in the regulation of endothelial junctions.